Anthracyclines represent a class of naturally occurring bioactive compounds derived from bacteria of the genus Streptomyces. Several anthracyclines were clinically demonstrated to be effective anti-neoplastic agents that can be employed for the treatment of a wide range of cancers including inter alia breast cancer, ovarian cancer, lung cancer, and hematological malignancies such as leukemias and lymphomas. In addition, members of this class of compounds were also shown to be useful in bone marrow transplants and during stem cell transplantation. Examples of such therapeutically relevant anthracylines include inter alia daunorubicin, idarubicin (i.e. 4-demethoxydaunorubicin), doxorubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and caminomycin.
4-Demethoxydaunorubicin (idarubicin) having the chemical structure of formula (I) (cf. below) is an analog of daunorubicin that interferes with nucleic acid synthesis by intercalating into DNA and interacts with the enzyme topoisomerase II. The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity, which results in an increased rate of cellular uptake compared with other anthracyclines. In combination with cytosine arabinoside 4-demethoxydaunorubicine is the current first line therapy of acute myeloid leukemia.
wherein An− represents an anion such as chloride.
Available methods for the chemical synthesis of 4-demethoxydaunorubicin (idarubicin) are generally based on the coupling of the aglycone of the compound (i.e. the non-sugar component) and the protected and activated daunosamine (i.e. 3-amino-2,3,6-trideoxy-L-lyxo-hexose; the sugar component) in the presence of silver triflate (AgOSO2CF3), trimethylsilyl-triflate ((CH3)3SiOSO2CF3), or a mercuric oxide-mercuric bromide system (HgO—HgBr2). The aglycone may, for example, be synthesized using either anthracenetetrone or isobenzofurane as starting material. However, such synthesis methods are complex due to the creation of optically active centers at carbons C7 and C9.
Alternative methods for the synthesis of 4-demethoxydaunorubicin utilize the aglycone of daunorubicin, which is prepared by the acidic hydrolysis of daunorubicin. In case, daunorubicin is subjected to acid degradation, the amino sugar daunosamin can be obtained separately, which is subsequently used, after chemical modification, for the glycosylation of the modified aglycone.
The first methods available for replacing the 4-CH3O (4-MeO) aglycone group for hydrogen (and other substituents such as NH2) involved demethylation of daunorubicinone, sulfonation of the resulting 4-demethyldaunorubicinone, and substitution of the 4-ArSO2O group for 4-ArCH2NH, followed by further reduction of the benzyl group to produce the 4-NH2 group (cf. U.S. Pat. No. 4,985,548). Performing a subsequent reductive deamination step results in the production of the aglycone of 4-demethoxydaunorubicin (cf. EP Patent No. 0328399 B1).
U.S. Pat. No. 5,587,495 discloses a reductive condensation reaction of 4-demethyl-4-trifluoromethanesulfonyl daunorubicinone (4-OTf daunorubicinone) and phenylphosphine/palladium or nickel complexes. Concomitantly, 4-R substituted daunorubicinones are obtained.

In a similar manner, the reductive carbonylation of 4-OTf daunorubicinone using the same complexes yields 4-COOR substituted daunorubicinones (cf. U.S. Pat. No. 5,218,130). If formate is used as reducing agent, the 4-OTf radical is replaced for hydrogen resulting in the production of 4-demethoxydaunorubicinone (cf. U.S. Pat. No. 5,103,029).
Hence, the established synthesis methods of 4-demethoxydaunorubicine all involve the fragmentation of the daunorubicin molecule in the aglycone component and the amino sugar component, separate chemical modification of the two components, and subsequent coupling. However, such synthesis scheme gives rise to an additional task, the generation of an optically active center at carbon C7. Typically, such synthesis schemes involve 10 to 12 different steps, thus reducing the overall yield of the final product to 6-8%.
U.S. Pat. No. 7,053,191 discloses an alternative synthesis route, in which derivatives of 4-demethyldaunorubicin (i.e. caminomycin), primarily N-trifluoroacetyl-4-demethyldaunorubicin were used as a starting compound. In this case, 4-OH group is removed from the full anthracycline molecule. To date, however, N-trifluoroacetyl-4-demethyldaunorubicin can only be obtained in reasonable amounts by means of complex chemical synthesis (cf. U.S. Pat. No. 4,188,377).
The advantageous modification of the synthesis route for caminomycin derivatives could be seen in the use of daunorubicin as starting material in order to reduce the number of synthesis steps required. However, so far it has not been possible to establish such synthesis scheme due to the lack of methods for the selective demethylation of the 4-MeO group of anthracyclines without concomitant cleavage of the glycosidic linkage at carbon C7.
One established method for demethylation of alkylphenyl ethers comprises the treatment of the alkylphenyl ethers with the strong Lewis acid AlCl3 in inert solvents (in particular, chlorinated hydrocarbons such as dichloromethane) at boiling point. Any attempt to apply this synthesis route to daunorubicin results in the removal of daunosamine followed by total destruction of the molecule.
Thus, there is still a need for new synthesis routes for the production of clinically efficient anthracycline compounds such as 4-demethoxydaunorubicine (idarubicin). In particular, there remains a need for less complex synthesis schemes involving a reduced number of reaction steps and thus resulting in an improved yield of the final product.
Accordingly, it is an object of the present invention to provide such methods.